Hepatitis C virus (HCV) is a frequent cause of chronic liver disease infecting 170 million persons worldwide. The World Health Organization considers Hepatitis C a "silent" epidemic because it can infect a patient for decades before being discovered. According to the CDC, 20 to 30% of people with chronic Hepatitis C will eventually face life-threatening symptoms. HCV represents a major public health problem and a significant economic burden in countries with high prevalence. Attempts to control infection with antiviral agents have been met with limited success particularly in genotypes 1 and 4 and in some ethnic populations. Moreover, health care budget constraints limit access to the costly treatment in developing countries with high prevalence. Therefore the need for an effective vaccine and new effective therapeutic strategies remains paramount. Vaccine development for HCV is limited by the quasispecies nature of the virus as well as lack of clear understanding of protective immune responses and the correlates of recovery from infection due to the asymptomatic nature of acute infection in most infected persons. Studies have shown that vigorous polyclonal cellular immune responses are associated with spontaneous recovery, whereas chronic infection is associated with weak immune response. We have identified a cohort of health care workers with known exposure to needle stick injury who had detectable CD4+and CD8+ responses although antibody seroconversion and vireamia could not be proven at any time point. The significance and function of these responses are not clear. The specific hypothesis is that repeated exposure to subclinical HCV infection leads to priming of specific immune response which can have a protective role. The specific aims are to:1) Characterize the patterns, fate and function of immune responses in subjects exposed to HCV infection. We will also correlate these responses to the outcome of exposure. 2) Test for HCV-specific T cell responses in a large cohort of subjects who remain uninfected and HCV-RNA negative despite repeated definite exposure to HCV to detect if these responses provide protection. In preliminary studies we demonstrated cellular immune responses in some exposed but persistently aviremic and antibody-negative individuals. 3) Identify the determinants of protection against HCV. We will perform phenotypic and functional characterization of HCV-specific T responses in addition to detailed characterization of HCV epitopes in exposed uninfected individuals with detectable immune responses. Our long-term goal is to mimic this response to develop vaccine strategies or therapeutic protocols capable of preventing persistent hepatitis C infection. [unreadable] [unreadable] [unreadable]